The classical cannabinoid Δ9-Tetrahydrocannabinol (Δ9-THC) is the major active constituent extracted from Cannabis sativa. The effects of cannabinoids are due to an interaction with specific high-affinity receptors. Presently, two cannabinoid receptors have been characterized: CB1, a central receptor found in the mammalian brain and a number of other sites in the peripheral tissues and CB2, a peripheral receptor found principally in cells related to the immune system. The CB1 receptor is believed to mediate the psychoactive properties, associated with classical cannabinoids. Characterization of these receptors has been made possible by the development of specific synthetic ligands such as the agonists WIN 55212-2 and CP 55,940.
In addition to acting at the cannabinoid receptors, cannabinoids such as Δ9-THC also affect cellular membranes, thereby producing undesirable side effects such as drowsiness, impairment of monoamine oxidase function and impairment of non-receptor mediated brain function. The addictive and psychotropic properties of some cannabinoids also limit their therapeutic value.
The pharmacological effects of cannabinoids pertain to a variety of areas such as the central nervous system, the cardiovascular system, the immune system and/or endocrine system. More particularly, compounds possessing an affinity for either the CB1 or the CB2 cannabinoid receptors are useful as agents: acting on the central nervous system and immunomodulators; in thymic disorders; vomiting; myorelaxation; various types of neuropathy; memory disorders; dyskinesia; migraine; multiple sclerosis; asthma; epilepsy; glaucoma; in anticancer chemotherapy; in ischemia and angor; in orthostatic hypotension; and in cardiac insufficiency.
Currently known bicyclic-cannabinoids and hexahydrocannabinol analogs contain a linear alkyl side chain at the C-3 position. This linear alkyl side chain at the C-3 position is a key pharmacophore in classical cannabinoids and considered essential for cannabinoid receptor activity. Structure Activity Relationship (SAR) studies suggest that in known cannabinoids, a 1,1-dimethylheptyl or a 1,2-dimethylheptyl side chain is optimal for cannabinoid activity. Additionally, known hexahydrocannabinol derivatives usually possess a carbonyl group in the C-9 position or a hydroxy group in the C-9 or C-11 positions. This “northern” functionality plays an important role on the cannabinoid structure, associated with cannabimimetic activity. The presence of a C-9 carbonyl group or a C-9 or C-11 hydroxy group is also known to significantly enhance the potency of cannabinoids.